Veterinary drugs can be administered to pigs, poultry and calves individually or as mass medication such as drinking water and feed medication. For the treatment of large groups of animals with antimicrobials and antiparasitic drugs, mass medication is preferred above parenteral administration as large numbers of animals can be medicated at the same time. Besides, other factors such as animal welfare and the avoiding of tissue damage and stress are important advantages.
Immediate therapeutical care for all diseased or endangered animals in the flock and a quick change of drug and/or dose are possible in case of drinking water medication compared to feed medication. Additionally, diseased animals tend to stop eating, while mostly they will continue drinking.
One of the problems frequently observed in feed medication is “carry-over” of the drug, which results in contamination of the unmedicated feed in the silo. This often leads to the disapproval of feed and even animals, when drugs concentrations above the maximal residue levels are found in the slaughterhouses. Another fact is that feed medication is often used prophylactically with the result that veterinary drugs are overused and the development of resistance occurs.
The main disadvantages of drinking water medication are the unprofessional use of medication and preparation of the solution or suspension by the farmer, the fact that drug uptake can vary dramatically in function of the animals and solubility and stability problems often occur in relation to the formulation. The drinking water medication needs to be physically and chemically stable over a sufficient period of time to allow a homogeneous dose administration and consequently an efficient therapy.
An important limitation for an application via drinking water is the low water solubility of many antimicrobials and antiparasitic drugs. Different mechanisms are described to improve water solubility of the drug such as complexation with cyclodextrins, production of self-emulsifying drug delivery systems, the use of phospholipid micro-emulsions and the formulation of solid solutions. However, these technologies cannot be applied for veterinary drug formulations as they are too expensive. Therefore there is a need for alternative preparation methods.
Compounds with a low water solubility are mainly formulated as liquids, such as dissolved in a valuable solvent, or provided as suspensions or emulsions. As a consequence, drugs are often low dosed in the formulation. Hence, and in order to obtain suitable dosing amounts, an important amount of liquid, containing large amounts of non-active ingredients (solvents, water) needs to be transported, which is very inefficient and expensive. Another disadvantage of liquid formulations is that they are often characterised by a limited stability. Therefore, the development of a solid formulation such as powders or granules to be redispersed in water is recommended.
Although solid formulations are known from the prior art, these often have the disadvantage of sedimentation after a certain period of time after application in the drinking water. Hence, a large amount of active ingredient is lost at the bottom of the drinking through.
For example WO2008000453 describes that aqueous slurries were prepared including a drug substance, maltodextrin and a surfactant, after which the mixtures were formulated by spray-drying these slurries. WO03074031 describes that maltodextrin with PEG400 and a drug are formed into solid granules (i.e. not a multiparticulate form).
However, it should be noted that the used maltodextrines in these publications have a low or medium DE (Dextrose Equivalent), i.e. being less than 10 (e.g. Novelose 330 has a DE of 5-7), while we discovered that maltodextrins having a DE of at least 10 are essential in the context of the present invention. As detailed in the examples, we have found that decreasing the DE value, results in an increased particle size of the multiparticulate formulations of the present invention, and thus an increased risk of sedimentation after suspension of the obtained particles.
Hence, we have now developed a novel production process for obtaining spray-dried solid pharmaceutical multiparticulate dosage forms that remain stable in drinking water or delivery systems for a long period of time. The present invention specifically relates to spray-dried pharmaceutical dosage forms, in contrast to freeze-dried pharmaceutical dosage forms such as for example disclosed in US20040228919 or WO2004078122. Evidently, freeze-drying and spray-drying are very different processes and compositions suitable for freezed-drying are not readibly suitable for spray-drying. The specific components of the formulations of the present invention are selected such that they render the formulations particularly suitable for spray-drying.
Key to the process of the present invention, and ultimately the new dosage form, is the combination of a non-ionic surfactant having an Hydrophilic Lipophilic Balance (HLB) of at least 8 and a maltodextrin having a DE (Dextrose Equivalent) value of at least 10. Said production process consists of two parts. In a first part, the particle size of the compound is decreased to the low micrometer range (below 10 μm) by wet milling with addition of said non-ionic surfactant, to improve the wettability of the compound. Hence, it is also key to the process that a non-solubilized active ingredient is used, since solubilized active ingredients, such as for example used in WO2010081815, cannot be milled. In the second part, the obtained suspension is spray-dried in the presence of maltodextrin to obtain an easily dispersible powder that remains physically stable during the time of administration via drinking water. As such, the obtained formulation can also be used for administration via proportioners. In proportioners, more concentrated suspensions are prepared and because of the low water solubility of many compounds, the preparation of such concentrated suspensions is difficult. A proportioner takes a small amount of a concentrated drug formulation redispersed in water and introduces it into the drinking water line. A 1% proportioner means that 1% of the concentrated dispersion (e.g. 1 ml) is diluted with 99% of drinking water (e.g. 99 ml)